All cells die. Traditionally, one thinks of cell death in the context of aging or pathology. However many of the cells that are normally produced during development are intentionally induced to die. This process, known as programmed cell death, is so fundamental to the normal development of an organism, that the same groups of cells can be found to die at the same developmental stage in all individuals. While much is known about the temporal and spatial patterns of cell death, little is known about the molecular mechanisms that mediate this process. Working with metamorphosing moths and negatively selected mouse T cells, we have cloned 16 different genes whose expression is dramatically elevated with the cell's decision to die. We have selected four of these genes for a detailed analysis since they are phylogenetically conserved and are good candidates for regulatory genes. In this proposal, we will use genetic, molecular and anatomical techniques to test the hypothesis that these genes represent essential cell death genes. An understanding of the genes that mediate programmed cell death is of interest because it represents a fundamental but poorly understood component of normal animal development. As well, there are also great potential clinical applications that could arise from these studies. Since all cells carry the genetic information required to commit suicide, the ability to manipulate this process in a lineage-specific manner is of obvious value. It may be possible to activate the suicide program of deleterious cells, such as cancer cells. Alternatively, it may be possible to block the inappropriate death of otherwise valuable cells, such as neurons in Alzheimer's Disease.